Challenges in Infective Endocarditis · THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW Challenges in Infective Endocarditis Thomas J. Cahill, MBBS,a Larry M. Baddour, MD,b Gilbert

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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Challenges in Infective Endocarditis
Thomas J. Cahill, MBBS,a Larry M. Baddour, MD,b Gilbert Habib, MD,c,d Bruno Hoen, MD, PHD,e
Erwan Salaun, MD,d Gosta B. Pettersson, MD, PHD,f Hans Joachim Schäfers, MD,g Bernard D. Prendergast, DMh

ABSTRACT

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Infective endocarditis is defined by a focus of infection within the heart and is a feared disease across the field of

cardiology. It is frequently acquired in the health care setting, and more than one-half of cases now occur in patients

without known heart disease. Despite optimal care, mortality approaches 30% at 1 year. The challenges posed by

infective endocarditis are significant. It is heterogeneous in etiology, clinical manifestations, and course. Staphylococcus

aureus, which has become the predominant causative organism in the developed world, leads to an aggressive form

of the disease, often in vulnerable or elderly patient populations. There is a lack of research infrastructure and funding,

with few randomized controlled trials to guide practice. Longstanding controversies such as the timing of surgery or

the role of antibiotic prophylaxis have not been resolved. The present article reviews the challenges posed by

infective endocarditis and outlines current and future strategies to limit its impact. (J Am Coll Cardiol 2017;69:325–44)

© 2017 by the American College of Cardiology Foundation.

I nfective endocarditis (IE) is a rare disease, but itsimpact is significant (1). It affects 3 to 10 per100,000 per year in the population at large, and

epidemiological studies suggest that the incidence isrising (2–5). In the United States, there are 40,000 to50,000 new cases each year, with average hospitalcharges in excess of $120,000 per patient (3). Despitetrends toward earlier diagnosis and surgical interven-tion, the 1-year mortality from IE has not improved inover 2 decades.

IE is an old problem in a new guise (6). In the pre-antibiotic and early antibiotic eras, it typicallyaffected young or middle-aged adults with underly-ing rheumatic heart disease or congenital heart dis-ease (CHD) (7). The development of antibiotics, thedecline of rheumatic heart disease, and advances inmedicine through the 20th century heralded a

m the aDepartment of Cardiology, Oxford University Hospitals, Oxford,

yo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota; cAi

PHM, La Timone Hospital, Cardiology Department, Marseille, France; eU

decine Hyacinthe Bastaraud, Inserm, Service de Maladies Infectieuses et

spitalier Universitaire de Pointe-à-Pitre/Abymes, Pointe-à-Pitre, France; fD

e Cleveland Clinic Foundation, Cleveland, Ohio; gDepartment of Thorac

dical Center, Homburg/Saar, Germany; and the hDepartment of Cardiology

ddour has received royalty payments from UpToDate, Inc.; and Editor-in-

urnal Watch Infectious Diseases). The other authors have reported that th

s paper to disclose.

nuscript received August 28, 2016; revised manuscript received October

change in the risk factor profile, patient de-mographic characteristics, and the microbiology ofIE. Prosthetic valve replacement, hemodialysis,venous catheters, immunosuppression, and intrave-nous (IV) drug use became the principal risk factors(8). The average patient was older and frailer, withincreasing comorbidities. Concurrently, staphylo-cocci overtook oral streptococci as the most frequentcausative organism (9,10).

In the 21st century, IE has continued to evolvesuch that it is now health care–acquired in >25% ofcases (9), while advances in cardiology have drivenfurther changes in the patient demographics andmanifestations of the disease. Alongside the emer-gence of cardiac implantable electronic devices(CIEDs), IE affecting complex devices has burgeoned(11). Similarly, transcatheter valve replacement is

United Kingdom; bDivision of Infectious Diseases,

x-Marseille Universite, URMITE, Marseille, France;

niversité des Antilles et de la Guyane, Faculté de

Tropicales, Dermatologie, Médecine Interne, Centre

epartment of Thoracic and Cardiovascular Surgery,

ic and Cardiovascular Surgery, Saarland University

, St. Thomas’Hospital, London, United Kingdom. Dr.

Chief payments from Massachusetts Medical Society

ey have no relationships relevant to the contents of

26, 2016, accepted October 30, 2016.

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ABBR EV I A T I ON S

AND ACRONYMS

18FDG-PET = 18

fluorodeoxyglucose positron

emission tomography

ACC = American College of

Cardiology

AHA = American Heart

Association

CDI = cardiac device infection

CHD = congenital heart disease

CI = confidence interval

CIED = cardiac implantable

electronic device

CoNS = coagulase-negative

staphylococci

CT = computed tomography

ESC = European Society of

Cardiology

HR = hazard ratio

IE = infective endocarditis

IV = intravenous

MRI = magnetic resonance

imaging

NVE = native valve infective

endocarditis

PVE = prosthetic valve

infective endocarditis

OPAT = outpatient parenteral

antibiotic therapy

OR = odds ratio

RCT = randomized controlled

trial

SPECT = single-photon

emission computed

tomography

TAVR = transcatheter aortic

valve replacement

TEE = transesophageal

echocardiography

TTE = transthoracic

echocardiography

Cahill et al. J A C C V O L . 6 9 , N O . 3 , 2 0 1 7

Challenges in Infective Endocarditis J A N U A R Y 2 4 , 2 0 1 7 : 3 2 5 – 4 4

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revolutionizing the management of valvularheart disease but may be associated withhigher rates of IE than surgically implantedprosthetic valves (12–14).

The present review outlines the challengesposed by contemporary IE in developedcountries, as well as the reasons why diag-nostic and treatment advances have failed tohave an impact on the disease. We highlightrecent data on the effect of changing anti-biotic prophylaxis guidelines, as well as thecurrent status of molecular and imagingdiagnostic strategies, and review policies forimproving service delivery and surgical out-comes. Reflecting the constant evolution ofthe disease, data on IE in 3 patient groupswere also examined that encapsulate someof the key challenges: those with trans-catheter aortic valve replacement (TAVR)-endocarditis, those presenting with stroke,and those with CIED infection. Finally, welook ahead and emphasize the future needfor enhanced clinical care pathways, inter-disciplinary collaboration, and research,which will be required for effective diseaseprevention, diagnosis, and cure.

PREVENTION

Prevention of IE is better than cure and re-quires insight into the mechanisms of dis-ease, the patient populations at risk, and aneffective preventive intervention. The dis-ease develops in 3 stages. The initiating stepis bacteremia, with bacteria commonlyentering the bloodstream via the mouth,gastrointestinal and urinary tracts, or theskin, through venous catheters or after aninvasive medical or surgical procedure. Thesecond step is adhesion: whereas the normalendothelial lining of the heart is resistant to

bacterial adhesion, bacteria (particularly gram-positive species) are able to adhere to abnormal ordamaged endothelium via surface adhesins. Thesespecialized proteins mediate attachment to extra-cellular host matrix proteins, a process which isfacilitated by fibrin and platelet microthrombi (15).Gram-positive bacteria also lack an outer membraneand have a thick surrounding peptidoglycan and aretherefore less sensitive to serum-induced killing.

Bacterial adhesion gives rise to colonization, inwhich cycles of bacterial proliferation occur in addi-tion to thrombosis, monocyte recruitment, andinflammation, leading to formation of a mature

vegetation (16). Many of the microorganisms associ-ated with IE (including staphylococci, streptococci,and enterococci but also less common pathogens,such as Candida species and Pseudomonas aeruginosa)produce biofilms, which allow bacterial populationsto embed within an extracellular polysaccharideslime-like matrix, with quorum sensing (chemicalcell-to-cell communication) and synchronized geneexpression promoting assembly and maturation.Once established, the biofilm protects bacteria fromhost immune defenses, impedes antimicrobial effi-cacy, and hides resistant persister organisms (17).Biofilm-forming capacity is now recognized as animportant determinant of virulence in the develop-ment of staphylococcal device-related infections (18).

ANTIBIOTIC PROPHYLAXIS. Preventive strategieshave historically focused on bacteremia. In 1909,Thomas Horder recognized that the mouth was amajor portal for bacterial entry, and, in 1935, strep-tococcal bacteremia was detected after dentalextraction (19,20). The first trials of penicillin pro-phylaxis were conducted in the 1940s and showedthat antibiotics reduced the incidence of bacteremiaafter dental extraction (21,22). Consequently, in 1955,the American Heart Association (AHA) publishedguidelines recommending antibiotic prophylaxis forpatients with rheumatic heart disease and CHD (23).Maintenance of good oral hygiene and antibioticprophylaxis for at-risk groups undergoing dentalextraction became the standard of care for 50 years.

Between 2007 and 2009, guidelines in the UnitedStates and Europe were substantially revised torestrict the use of antibiotic prophylaxis. There wereseveral reasons for these revisions. First, in the era ofevidence-based practice, there was (and remains) norandomized controlled trial (RCT) of antibiotic pro-phylaxis for prevention of infective endocarditis inthe context of dental extraction. Second, the efficacyof prophylaxis was questioned on the basis of anapparent failure rate of up to 50% (24). Third, theimportance of widespread antibiotic use as a contrib-utor to emerging resistance was gaining recognition,while the indications for prophylaxis had expandedsignificantly to encompass groups at moderate risk.Finally, the significance of dental procedures as acause of IE was questioned due to population studiesthat did not show dental intervention as a major riskfactor (25,26). In contrast, “everyday” bacteremia, dueto tooth brushing, chewing, and inadequate dentalhygiene, was recognized as a possible cause of IE. In acohort awaiting dental extraction (i.e., with dentaldisease), tooth brushing alone was sufficient to causebacteremia in 23% (27). The relative importance of rare

TABLE 1 Time Trend Studies Addressing the Changing Population Incidence of IE After Guideline Change

First Author, Year (Ref. #) Study Location Population/Diagnoses Analyzed Incidence Change?

Bikdeli et al., 2013 (37) United States All diagnoses of IE from MedicareInpatient Standard Analytic Files

No evidence of an increase in adjusted rates of hospitalization or mortality after2007 guideline change.

Dayer et al., 2015 (5);Thornhill et al.,2011 (38)

England, UnitedKingdom

All diagnoses of IE from NHS HospitalEpisode Statistics

In the 2015 analysis, there was an increase detected in the number of cases of IEabove the projected historical trend (by 0.11 case per 10 million people permonth). Statistical analysis identified June 2008 as the change point(3 months after the NICE guideline change).

De Simone et al., 2015(35); DeSimone et al.,2012 (34)

Olmsted County,Minnesota

Diagnoses of VGS IE from the RochesterEpidemiology Project

No evidence of an increase in VGS IE.

Duval et al., 2012 (33) France: Greater Paris,Lorraine, andRhône-Alpes

All diagnoses of IE and subgroups byspecific organisms

No evidence of an increase in VGS IE.

Mackie et al., 2016 (36) Canada Diagnoses of IE from Canadian Institutefor Health Information DischargeAbstract Database

No significant change in the rate of increase in IE cases after publication ofguideline change. Reducing incidence of VGS IE over time. Change pointanalysis did not identify guideline change as a significant inflection point.

Pant et al., 2015 (2) United States Diagnosis of IE using NationwideInpatient Sample

Significant increase in the rate of increase in streptococcal IE after 2007(change in the slope before and after: 1.37; 95% CI: 0.69–2.05; p ¼ 0.002).No change point analysis.

Keller et al., 2016 (156) Germany All patients hospitalized with acute orsubacute IE

Yes. Continuous small increase in incidence of IE before guideline changebetween 2006 and 2010, with an accelerated increase in incidence followingguideline change, between 2011 and 2014.

Van den Brink et al.,2016 (157)

Netherlands All patients with IE identified from thenational healthcare insurancedatabase

Yes, significant increase in IE above the projected historical trend, coincidingwith change in ESC guidelines in 2009 (rate ratio 1.327, 95% CI: 1.205–1.462; p<0.001). Increased proportion of streptococcal IE followingguideline change.

CI ¼ confidence interval; IE ¼ infective endocarditis; NHS ¼ National Health Service (United Kingdom); NICE ¼ National Institute for Health & Care Excellence (United Kingdom); VGS ¼ viridansgroup streptococci.

J A C C V O L . 6 9 , N O . 3 , 2 0 1 7 Cahill et al.J A N U A R Y 2 4 , 2 0 1 7 : 3 2 5 – 4 4 Challenges in Infective Endocarditis

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and high-magnitude bacteremia (e.g., caused bydental extraction) compared with common, low-levelbacteremia in the pathogenesis of IE remainedpoorly defined. Therefore, in the United States andEurope, antibiotic prophylaxis was restricted to thoseat highest risk (28,29). Meanwhile, in the UnitedKingdom, antibiotic prophylaxis was abandonedentirely in a highly controversial decision bythe U.K. National Institute for Health and Care Excel-lence (30,31).

EFFECTS OF CHANGING GUIDELINES ON THE

INCIDENCE OF IE. Several studies have now exam-ined the effect of restricting oral antibiotic prophy-laxis on the incidence of IE (Table 1). In France, whereantibiotic prophylaxis was limited to high-risk groupsas early as 2002, a survey approach was used to gatherdata on all cases of IE across several different regions(32,33). The incidence of IE in 3 survey years (1991,1999, and 2008) was found to be stable at 35, 33, and32 cases per million, suggesting no significant changeafter restriction of oral antibiotic prophylaxis.Importantly, the number of cases caused by oralstreptococci was also stable.

In 2007, the American College of Cardiology (ACC)/AHA restricted antibiotic prophylaxis in the UnitedStates to patients with prosthetic valves, CHD, andprevious IE, as well as cardiac transplant recipientswith valvulopathy (29). Using data from the Rochester

Epidemiology Project, DeSimone et al. (34,35)analyzed the incidence of IE due to viridans groupstreptococci before and after this change. No increasedincidence was identified and, conversely, there wasa drop in incidence from 3.6 per 100,000 person-yearsfrom 1999 to 2002 to 1.5 per 100,000 person-years from2011 to 2013. Similarly, 2 population studies fromCanada and the United States found no evidence for achange point in the incidence of IE coinciding with theACC/AHA guideline amendment (36,37).

In contrast, 2 nationwide epidemiological studiesfrom the United States and the United Kingdom havegiven cause for concern. Using the Nationwide Inpa-tient Sample, Pant et al. (2) identified a statisticallysignificant increase in the incidence of IE caused bystreptococci, although there was no significantchange in the (upward) trend in total hospitalizationsor in staphylococcal endocarditis. This study includedboth non–viridans group streptococci and enterococciin the incidence calculations, however, and did notperform change point analysis to confirm that thechange in rate coincided with the ACC/AHA guidelineamendment. Furthermore, the investigators had noaccess to antibiotic prophylaxis prescribing data toconfirm that this rate had declined.

In the United Kingdom, where national guidanceadvised against use of antibiotic prophylaxis in March2008, early analyses signaled no rise in the incidence ofIE (38). In 2015, however, Dayer et al. (5) published an

TABLE 2 ACC/AHA and ESC Guidelines on Use of Antibiotic Prophylaxis for the Prevention of IE

ACC/AHAClass, Level of

Evidence ESCClass, Levelof Evidence

Dental procedures thatinvolvemanipulation ofgingival tissue,manipulation of theperiapicalregion of teeth, orperforationof the oral mucosa*

1. Patients with prostheticcardiac valves

2. Patients with previous IE3. Cardiac transplant recipients

with valve regurgitation due to astructurally abnormal valve

4. Patients with CHD, includinga. Unrepaired cyanotic

CHD, including palliativeshunts and conduits;

b. Completely repaired CHDrepaired with prostheticmaterial or device, whether placedby surgery or catheter interven-tion, during the first 6 months afterthe procedure; or

c. Repaired CHD with residualdefects at the site or adjacent tothe site of a prostheticpatch or prosthetic device

IIa, B 1. Patients with any prostheticvalve, including a transcatheter valve,or those in whom any prostheticmaterial was used for cardiac valve repair

2. Patients with previous IE3. Patients with CHD, including

a. Any type of cyanotic CHDb. Any type of CHD repaired with

a prosthetic material, whetherplaced surgically or by using percutaneoustechniques, up to 6 months after the procedure,or lifelong if residual shunt orvalvular regurgitation remains

IIa, C

Vaginal delivery† 1. Patients with prosthetic cardiacvalve or prosthetic material usedfor cardiac valve repair‡

2. Patients with unrepaired andpalliated cyanotic CHD, includingsurgically constructed palliativeshunts and conduits‡

IIa, C Not recommended. “During delivery the indication forprophylaxis has been controversial and, given the lackof convincing evidence that infective endocarditis is relatedto either vaginal or caesarean delivery, antibioticprophylaxis is not recommended” (145).

III, C

*ACC/AHA guidelines on valvular heart disease 2014 and ESC guidelines on infective endocarditis 2015. †ACC/AHA management of adults with congenital heart disease 2008 (146); and ESCmanagement of cardiovascular diseases in pregnancy 2011 (145). ‡Infective endocarditis prophylaxis at the time of vaginal delivery is controversial and not included as an indication in the ACC/AHA guidelines on valvular heart disease 2014 or the main ESC 2015 guidelines.

CHD ¼ congenital heart disease; IE ¼ infective endocarditis.



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extended analysis looking at National Health Servicehospital discharge diagnoses up to 2013. Antibioticprophylaxis dropped from 10,900 prescriptions permonth to 2,236 prescriptions per month after intro-duction of the U.K. National Institute for Health andCare Excellence guidelines. In parallel, there was asignificant rise (above the projected trend) in thenumber of IE cases, by 0.11 case per 10 million persons(or an additional 35 cases in England) per month. Sta-tistical analysis identified June 2008 (3 months afterimplementation of the new guidelines for the use ofantibiotic prophylaxis) as the point of change, but itwas not possible to confirm that these cases were dueto oral streptococci because microbiological data wereunavailable.

These data are observational and cannot establish acausal link between restriction of antibiotic prophy-laxis and incidence of IE. They are subject to con-founding, for example, by increasing numbers ofdevice implants, although this factor has beenadjusted for in some studies. Despite the longstandingcontroversy and difficulty with observational data, arandomized trial is highly unlikely due to cost, logis-tics, and ethical debate as to whether true equipoiseexists to allow conduct of a placebo-controlled trial.

The current pragmatic approach (endorsed by theACC/AHA and the European Society of Cardiology[ESC]) (Table 2) is to limit prophylaxis to individuals athighest risk on the basis of the underlying cardiaccondition. In our view, this approach correctly bal-ances the risks and benefits of individual and popu-lation antibiotic use. Importantly, this classificationomits patients who have noncardiac risk factors (e.g.,those who are immunocompromised) and who may beat increased risk of both IE and poor outcome if thedisease develops. There are few data to guide specificpractice in these groups, and a tailored approach forindividual patients remains appropriate, according toclinical circumstances (39,40).

PREVENTION OF HEALTH CARE–ASSOCIATED IE.

Health care–associated IE accounts for an increasingproportion of cases and requires specific strategies forprevention. The affected patient demographic isolder, and most have either degenerative valve dis-ease or no intrinsic cardiac risk factors. Instead, themost frequent risk factors are hemodialysis, cancer,diabetes mellitus, and the presence of a CIED (9,41).Staphylococcus aureus is the causative organism inapproximately one-third of cases, and the overall


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proportion of IE due to S aureus in the United Statesrose from 24% to 32% between 1998 and 2009 (3).S aureus is consistently an independent risk factor forin-hospital death (42). In keeping with the affectedpatient population and underlying microbiology, thein-hospital mortality for patients with health care–associated IE is significantly higher than forcommunity-acquired infection (31.1% vs. 20.3%;p < 0.01) (9).

Reduction of health care–acquired bacteremia isthus a logical target. Longitudinal studies fromDenmark found that an increase in S aureus bacter-emia occurred from 3 to 20 per 100,000 person-yearsbetween 1957 and 1990, mirroring increasing rates ofhospital admission and invasive medical procedures(although rates have now plateaued in the developedworld) (43,44). In the United States, 10% to 20% of thepopulation are persistent carriers of S aureus (45). Forcentral line–associated bloodstream infection,practice-changing interventions to improve adher-ence to sterile practice (hand hygiene, barrier pre-cautions, and antisepsis) have already significantlyreduced rates of bacteremia (46,47). Bundled in-terventions to reduce catheter-related bloodstreaminfection in high-risk groups, such as those under-going hemodialysis, could translate into a majorimpact on the incidence of IE (48,49).

Novel approaches to prevention of bacteremia andstrategies to target adherence are urgently required(50). Innovative material technologies, which preventinteraction of bacteria with prosthetic surfaces (so-called low-fouling coats) or contain long-lastingbactericidal coatings, hold promise but have so farfailed to translate into clinical practice. Indeed,enthusiasm for antibacterial coatings has beentempered by experience with the Silzone valve (St.Jude Medical, St. Paul, Minnesota), which had a silver-coated sewing ring, but had to be recalled within 3years of its release in 1997 due to an increased risk ofthrombosis and paravalvular leak (51,52). Further-more, this outcome was seen as a failure of regulatoryapproval processes for modification of existing valves.A vaccine targeted at bacterial components has longbeen seen as attractive for patients at high risk ofbacteremia. However, 2 candidate S aureus vaccinesfailed to demonstrate efficacy in Phase III clinicalstudies, with 1 failing to reach an efficacy endpoint(prevention of S aureus bacteremia in patients under-going hemodialysis) and another leading to increasedmortality in patients undergoing median sternotomywho developed staphylococcal infection (53,54). Morepositively, a new composite vaccine targeting 5 com-ponents of S aureus has recently been shown to behighly protective in mouse models (55).

DIAGNOSIS

Reaching a rapid and accurate diagnosis in cases ofsuspected IE is a central challenge of the disease.Delayed diagnosis and initiation of therapy lead tocomplications and worse clinical outcomes (56–58).Clinical presentation is notoriously diverse, rangingfrom acute sepsis to an indolent low-grade febrileillness, a heart failure syndrome, or stroke. Further-more, the modified Duke criteria, originally designedfor research purposes and advocated by AHA guide-lines for evaluation of patients with suspected IE,have a lower sensitivity for patients with prostheticvalve endocarditis (PVE) or cardiac device infection(CDI) (59,60). Up to 30% of patients with subse-quently proven IE are labeled as “possible” due toequivocal or negative findings on echocardiographyor blood cultures (61,62). Definitive cardiac imagingand microbiology are therefore of integral importancein making the diagnosis and also inform risk stratifi-cation, direct management, identify complications,and assist with monitoring therapy. Key advanceshave been made in recent years in reaching a defini-tive diagnosis in patients who fall into the “possible”group according to the Duke criteria.

IMAGING. Echocardiography remains the cornerstoneof imaging and is rapid, straightforward, and, in manycases, diagnostic (63). Transthoracic echocardiogra-phy (TTE) is the recommended initial modality ofchoice for both native valve infective endocarditis(NVE) and PVE. For suspected NVE, TTE has a sensi-tivity of 50% to 90% and a specificity of 90%. For sus-pected PVE, the sensitivity of TTE is lower, at 40% to70%, yet it provides value in assessment of ventricularsize and function, hemodynamic severity of valve le-sions, and in the diagnosis of anterior prosthetic aorticvalve abscesses, which may be difficult to visualize ontransesophageal echocardiography (TEE). TEE is indi-cated when TTE is positive or nondiagnostic, whencomplications are suspected, or when intracardiacdevice leads are present. For suspected NVE, TEE has asensitivity of 90% to 100% and a specificity of 90% fordetection of vegetations, and it is superior to TTE fordetection of complications, such as perforations, ab-scesses, and fistulae. In PVE, a recent meta-analysisreported a pooled sensitivity of only 86% (95% confi-dence interval [CI]: 77% to 92%) for TEE in making thediagnosis (64), and other imaging modalities areemerging to help make or exclude the diagnosis incases in which TEE is nondiagnostic. Even when ab-normalities are detected, it can be difficult to differ-entiate nodules from small vegetations or distinguishsigns of infection from post-operative changes.

FIGURE 1 Cardiac CT in IE

A 78-year-old man was admitted with infective endocarditis (IE) on an aortic bioprosthesis. Blood culture specimens were positive for Enterococcus faecalis. Initial

transthoracic echocardiography imaging demonstrated a suspected anterior and intercoronary pseudoaneurysm on parasternal long-axis (A) and short-axis (B) views

(arrows). On transesophageal echocardiography (C and D), a vegetation (C, red arrow) and pseudoaneurysm (D, white arrow) were visualized, although the insertion of

the vegetation was not apparent due to shadowing from the frame of the bioprosthesis. On cardiac computed tomography (CT) scanning, the vegetation was seen in

the left ventricular outflow tract view (E, red arrow), which also demonstrated the insertion of the vegetation on the anterior leaflet. The short-axis cardiac CT view

(F) confirmed the anterior pseudoaneurysm and 3-dimensional reconstruction (G) allowed delineation of the position of the pseudoaneurysm relative to the coronary

arteries. AO ¼ aorta; LA ¼ left atrium; LV ¼ left ventricle; RV ¼ right ventricle.



330

Cardiac computed tomography (CT) scanning is thekey adjunctive modality for use when the anatomy isnot clearly delineated according to echocardiography,and it now has a Class II, Level of Evidence: B recom-mendation for use in IE in the 2014 ACC/AHA valvularheart disease guidelines (Figure 1) (59). Cardiac CT isequivalent (and possibly superior) to TEE for demon-strating paravalvular anatomy and complications (e.g.,paravalvular abscesses or mycotic aneurysms) and issubject to fewer prosthetic valve artifacts than echo-cardiography (65–67). This approach may help withplanning surgical strategy, and concurrent CT angiog-raphy allows exclusion of significant coronary diseasein younger patients. Detection of paravalvular lesionsby using CT imaging is now amajor diagnostic criterionin the 2015 ESC guidelines on IE (68).

Combining CT imaging with metabolic imaging by18-fluorodeoxyglucose positron emission tomography(18FDG-PET) or leukocyte scintigraphy (radiolabeledleukocyte single-photon emission computed tomog-raphy [SPECT]) to show regions ofmetabolic activity orinflammation, respectively, is a hugely promisingapproach in patients who, according to the Dukecriteria, have “possible” IE or suspected CDI (Figure 2).Several studies have now investigated the sensitivityand specificity of PET/CT or SPECT/CT imaging in thissetting. In a cohort of 72 patients with suspected PVE,18FDG PET/CT imaging had an overall sensitivity of

73% and a specificity of 80% (69). The addition of“abnormal prosthetic valve 18FDG-PET signal” as adiagnostic criterion increased the sensitivity of themodified Duke criteria from 70% to 95%, reducing thenumber of patientswith “possible IE” from56% to 32%.In a Spanish cohort of patients with suspected PVE orCDI, 18FDG-PET/CT (angiography) demonstrated anoverall sensitivity and specificity of 87% and 90%,respectively, and increased the sensitivity of themodified Duke criteria from 51% to 91% (70). Use ofPET/CT imaging allowed reclassification of 90% ofcases (35 of 39) with “possible” IE and provided aconclusive diagnosis in 95% of cases overall. Forleukocyte scintigraphy with SPECT/CT imaging, asensitivity of 90% and a specificity of 100% have alsobeen reported (71). When directly compared in a cohortwith suspected PVE and inconclusive echocardiogra-phy findings, 18FDG-PET/CT imaging had highersensitivity than SPECT/CT imaging, but SPECTdemonstrated higher specificity (72). The significanceof abnormal 18FDG-PET/SPECT imaging has beenrecognized in the 2015 ESC guidelines; a positive signalat the site of a prosthetic valve (if implanted>3monthspreviously) is now regarded as a major diagnostic cri-terion for PVE.

Routine cross-sectional imaging of the brain, chest,spine, and viscera can be diagnostic and can changemanagement. Imaging cohort studies suggest that


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patients with IE have a high incidence of subclinicalcomplications, such as embolism, hemorrhage, orabscess. Routine cerebral magnetic resonance imag-ing (MRI) identifies abnormalities in 80% of patients,and, in 1 prospective study, upgraded 14 (26%) of 53patients from “possible” to “definite” IE (73).In another series, CT cerebral angiography identifiedintracranial mycotic aneurysms in 32% of patientswith left-sided endocarditis, of whom 50% subse-quently underwent endovascular or neurosurgicalintervention (74). Similarly, MRI imaging of theabdomen identified abnormalities in the spleen, liver,or kidneys in 34% of patients (75). Evidence of em-bolism by cross-sectional imaging is a novel minordiagnostic criterion in the ESC 2015 guidelines.

Multimodality assessment by cross-sectionalimaging, cardiac CT, and 18FDG-PET or SPECT has thepotential to improve diagnosis and detection of com-plications in patients with suspected IE (Figure 2). Wesee CT and 18FDG-PET/CT becoming widely used fordiagnosis in the “Duke possible” subgroup of patientsand for CDI (see later discussion). There are drawbacks,however. Metabolic imaging cannot accuratelydiscriminate between sterile inflammation and infec-tion, and it is therefore of limited use in the early post-operative period. False-positive findings for PET/CTimaging have been reported after cardiac surgery dueto post-pericardiotomy syndrome and prosthetic valvethrombosis; they have also been reported at the site ofan aortic graft. Access to advanced imaging is oftenlimited, and there is a risk that logistical hurdles maydelay definitive surgical intervention. Finally, identi-fying which patient groups derive the most clinicalbenefit from advanced imaging (and through preciselywhich modalities) remains to be established.

MICROBIOLOGY. Health care–associated organismshave increasingly defined the microbiology ofcontemporary IE. S aureus is now the most commoncausative organism and accounts for approximately30% of cases (9,10). S aureus endocarditis is charac-terized by aggressive disease with increased risk ofembolism, stroke, persistent bacteremia, and death(76). S aureus is also the most common cause of PVE,often requiring redo surgery, and is associated withmortality rates approaching 50% in some centers(77,78). Coagulase-negative staphylococci (CoNS) havea rising incidence of approximately 10% and play amajor role in PVE occurring in the first year after theinitial procedure (79,80). Importantly, CoNS haveemerged as a cause of NVE, as well as PVE (81). Theyare often methicillin resistant and, in the case ofStaphylococcus lugdunensis, associated with highlydestructive valvular and perivalvular lesions. Oral

streptococci comprise approximately 20% of cases,other streptococci approximately 10%, and entero-cocci a further 10%. HACEK organisms (Haemophilusspecies, Aggregatibacter species, Cardiobacteriumhominis, Eikenella corrodens, and Kingella species),zoonoses, and fungi collectively account for <5% ofcases.

Approximately 10% to 20% of patients have nega-tive blood culture findings at presentation, leading todiagnostic uncertainty. Negative results on bloodcultures may occur due to previous antibiotic use,infection with fastidious intracellular organisms orfungi, or an alternative diagnosis. The incidence ofblood culture–negative IE may drop with increasinguse of newer blood culture techniques, which allowdirect identification of bacterial species by massspectroscopy and are significantly faster than stan-dard culture methods (82).

A rigorous diagnostic approach to patients withblood culture–negative IE allows a causative organ-ism to be identified in two-thirds of patients (83). Thefirst stage is serological testing for zoonotic agents,specifically Coxiella burnettii (causing Q fever), Bar-tonella quintana and Bartonella henselae, Brucellaspecies, Myocoplasma species, and Legionella species.If serological findings are positive, blood polymerasechain reaction targeting the causative bacteria shouldbe undertaken. If serological findings are negative,molecular testing of blood or excised valve material isvaluable, including broad polymerase chain reactionfor bacterial 16S ribosomal ribonucleic acid genes andtargeted polymerase chain reaction for Tropherymawhipplei, Bartonella species, and fungi. If microbio-logical investigation remains negative, considerationshould be given to autoimmune disease, and testingfor antinuclear antibodies and rheumatoid factorinitiated. In a French cohort of 759 patients withblood culture–negative IE, 476 patients ultimatelyhad an identified etiologic agent, most commonlyzoonoses (229 Q fever, 86 Bartonella species). Twelvepatients were diagnosed with T whipplei, 8 withfungi, and 70 with common bacteria; 19 (2.5%) werefound to have noninfectious endocarditis caused byautoimmune disease or marantic endocarditis (83).

MANAGEMENT

Management of patients with IE is both a clinicaland logistical challenge. Delivery of optimal care re-quires an administrative infrastructure and theinvolvement of multiple hospital specialists,including cardiologists, surgeons, infectious diseasephysicians, microbiologists, nephrologists, neurolo-gists, and radiologists. Optimizing service delivery

FIGURE 2 Integrated Imaging Strategy in Patients With Suspected IE

Definite IE

Consider furtherimaging for detection

of complications or surgical planning

Cardiac CTCT/MRI

1.2.

TTE & TEE

Possible IE

Cardiac CT18F-FDG PET/CT or SPECT/CT*CT/MR cross-sectional imagingRepeat TEE

1.2.3.4.

Further diagnostic imaging

Definitive diagnosis

* In patients with prosthetic valves or cardiac implantable electronic devices

Clinical evaluation

Rejected IE

A

(A) Integrated imaging strategy in patients with suspected infective endocarditis (IE). In the challenging subgroup of patients with possible IE after initial evaluation by

transthoracic echocardiography and transesophageal echocardiography (TEE), cardiac CT imaging, metabolic imaging, or cross-sectional imaging of the head and

viscera by CT scanning or magnetic resonance imaging (MRI) may help to reach an early definite diagnosis. Panels B to F: 18-Fluorodeoxyglucose positron emission

tomography (18FDG-PET/CT) imaging for diagnosis. A 54-year-old woman with a history of mitral valve replacement 5 years previously was admitted with features of

acute left ventricular failure. Transthoracic echocardiography on admission revealed severe intraprosthetic regurgitation. The TEE bicommissural (B and C) and

3-dimensional atrial (D) views revealed a leaflet perforation (arrow) and severe regurgitation but no evidence of vegetation. Blood cultures on admission were

negative, although inflammatory markers were raised. Antibiotics for suspected blood culture-negative IE were started, and 18FDG-PET/CT imaging confirmed the

diagnosis with focal signal uptake on the mitral bioprosthesis (E and F, red arrow). Panels G to K: Cross-sectional imaging by CT or MRI (or metabolic imaging) scans

may assist with detection of complications, such as abscess, mycotic aneurysm, infarct, or hemorrhage in patients with definite IE. 18FDG-PET/CT for detection of

complications of IE. A 65-year-old woman with a mitral bioprosthesis was diagnosed with Staphylococcus aureus IE. TEE revealed a mobile vegetation with leaflet

prolapse and severe regurgitation (G and H). On 18FDG-PET/CT imaging, there was 18FDG signal from the mitral bioprosthesis (I and J, white arrow) and evidence of a

splenic abscess (I and K, red arrow). SPECT ¼ single-photon emission computed tomography; other abbreviations as in Figure 1.

Continued on the next page



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FIGURE 2 Continued


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and early decision making have the potential toimprove clinical outcomes, leading to calls for for-mation of “IE teams,” modeled on the heart teamapproach to coronary and heart valve disease (84).

Introduction of a formalized multidisciplinary teamapproach in Italy, defined by initial evaluation within12 h, early surgery (within 48 h) if indicated, andweekly review, led to a reduction in in-hospital (28%vs. 13%; p ¼ 0.02) and 3-year (34% vs. 16%; p ¼ 0.0007)mortality, despite patients being older and havingmore comorbidities (85). Similarly, a French multidis-ciplinary team approach to standardizing care,including antibiotic protocols and indications for sur-gery, reduced 1-yearmortality from 18.5% to 8.2% (86).

Centralized care concentrated in tertiary centerswith advanced diagnostic imaging, surgical expertise,and higher throughput clearly has a role in complexcases and may also be universally beneficial. Thereare arguments against this model, however, such asdelays during transfer and loss of local expertise.Reconfiguration toward a system of centralized IEcare (or a hub-and-spoke model, with central multi-disciplinary review) should therefore be instituted onthe basis of evidence. The efficacy of centralized careto improve decision making, time to surgery, curerates, and short- and long-term outcomes could bereadily tested in a before-and-after study.

ANTIBIOTIC THERAPY. Before the discovery of peni-cillin, IE was an untreatable disease (87,88). Effectivemicrobial clearance requires bactericidal antibioticregimens, usually in combination. Detailed empiricaland organism-specific antibiotic protocols are beyondthe scope of the present review but are provided inthe latest AHA and ESC guidelines (68,89).

The importance of balancing efficacy of treatmentwith the overall risk and toxicity of prolonged inpa-tient therapy is increasingly recognized. Emergingevidence supports short-course or stepped-downantibiotic treatment in selected groups. In patientswith uncomplicated IE caused by oral streptococciand normal renal function, a combination of a peni-cillin or ceftriaxone with an aminoglycoside for a totalof 14 days is safe and effective (90). Similarly, a2-week course of penicillin monotherapy orpenicillin-aminoglycoside in combination is effectivefor uncomplicated methicillin-sensitive S aureusright-sided IE (91).

There are increasing data to suggest that the use ofaminoglycosides may be causing harm without clearclinical benefit. In a 2006RCT of daptomycin comparedwith conventional therapy (penicillin or vancomycinwith initial gentamicin) for S aureus bacteremia orright-sided endocarditis, daptomycin was shown to benoninferior. Importantly, renal dysfunction occurredin 11% of those treated with daptomycin comparedwith 26% of the conventional therapy arm (92,93).Aminoglycosides have now been removed from theESC and AHA guidelines for the treatment ofmethicillin-sensitive S aureus or methicillin-resistantS aureus NVE. Although aminoglycosides have histor-ically been widely used for enterococcal IE, theincreasing frequency of resistance (25% to 50% of iso-lates in recent studies), along with the recognition ofpotential harm, led the ESC 2015 guideline committeeto identify ampicillin and ceftriaxone (Class IBrecommendation) as the treatment of choice foraminoglycoside-resistant Enterococcus faecalis. Thisrecommendation is supported by large observationalstudies showing that ampicillin/ceftriaxone is as



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effective as ampicillin/gentamicin, with reducedlevels of nephrotoxicity (94,95).

Further research is needed to determine whetheradditional patient groups may be suitable for short-ened courses of antibiotic therapy. For example, inpatients who have undergone successful surgery andhave negative valve culture findings suggesting suc-cessful microbial elimination (after initially positiveblood culture results), it may be safe to stop antibi-otics after 2 weeks (96,97). However, current AHAguidelines suggest that the remaining duration ofantibiotics be given (including administration beforesurgery), but this suggestion is indicated on the basisof Level C evidence (89).

Reduction of in-hospital stays may also be ach-ieved through an early switch to regimens of oralantibiotics with good bioavailability. In IV drug users,there are RCT data supporting the safety and efficacyof oral ciprofloxacin and rifampicin for uncompli-cated methicillin-sensitive S aureus NVE, althoughincreasing rates of fluoroquinolone resistance limitapplicability (98). The POET (Partial Oral Treatmentof Endocarditis) trial is an ongoing Danish multi-center study designed to address whether step-downto oral treatment is safe after the first 10 days of IVantibiotics in staphylococcal, streptococcal, orenterococcal NVE. Four hundred patients will berandomized to receive 4 to 6 weeks of IV treatment,compared with step-down to oral therapy after aminimum of 10 days, with a primary endpoint of all-cause mortality, unplanned cardiac surgery, embo-lism, or relapse of positive blood culture findings (99).

Early hospital discharge is frequently facilitated bythe use of outpatient parenteral antibiotic therapy(OPAT). OPAT can be initiated in specific patientsafter completion of the first 2 weeks of treatment,after which the risk of complications is reduced.OPAT is contraindicated in patients with heart failure,complex infection, high risk of embolism, neurolog-ical complications, or renal impairment (100–102).Facilitated readmission pathways, as well as closenursing and medical monitoring, are necessary.

The major challenges to successful antibiotictherapy are bacterial tolerance and antibiotic resis-tance. Tolerance occurs when phenotypic variants ofbacteria persist despite antibiotic therapy, and theyresume growth and infection once antibiotic con-centrations fall. There are multiple underlyingmechanisms, including the very high bacterial den-sity and poor antibiotic penetration within vegeta-tions, low bacterial metabolic activity, andproduction of protective biofilms on prosthetic ma-terial (103). The risk of tolerance, combined withrelatively slow bactericidal antibiotic effects,

underlies the historical requirement for 4 to 6 weeksof parenteral antibiotic therapy.

Novel strategies are required to prevent and treatIE caused by biofilm-forming strains of multidrug-resistant S aureus. These strategies may include theinitial inhibition of bacterial adhesion to both livingand inert surfaces (thus reducing further biofilmdevelopment), disruption of biofilm architecture, andantipathogenic or signal interference approachesinvolving inhibition of quorum sensing (18). Preven-tion of bacterial adhesion at the time of intracardiacdevice insertion is key and may be achieved by usingimplants coated with various adhesion inhibitors.However, despite inhibiting biofilm formationin vitro, antibiotic-, silver ion–, and silver nano-particle–coated implants have proved to be ineffec-tive and poorly tolerated in humans. Disruption ofbiofilm architecture may be a more promisingapproach, and several compounds, including humanmonoclonal antibodies such as TRL1068, arecurrently being assessed. Treatment of establishedbiofilm using a combination of TRL1068 with dapto-mycin in an in vivo murine model (in which biofilmwas formed by infection with methicillin-resistantS aureus) significantly reduced the adherent bacte-rial count compared with daptomycin alone (104).SURGERY. Surgery is performed for the specific in-dications of progressive valve and tissue damage,uncontrolled infection, and high risk of embolism. Theobjectives are as follows: to remove infected tissue,foreign material, and hardware; clear and debrideparavalvular infection and cavities; restore cardiacintegrity and valve function; and remove threateningsources of embolism. Although various surgical tech-niques have been used (e.g., mitral valve repair, aortichomograft implantation), a clear long-term advantageof one technique has yet to be proven. Regardless ofapproach, the long-term results are inferior to electivevalve surgery: 10-year survival ranges from 40% to60% (105,106). It remains unclear whether this latemortality relates to late prosthetic valve complica-tions, extracardiac manifestations of the disease, orpersistence of the biofilm complex.

Surgery is currently performed in 50% to 60% ofpatients, and 6-month survival rates are >80%(107,108). The indications for surgery have been pre-dominantly derived from historical observationalstudies that show benefit in patients with valvedysfunction causing heart failure, uncontrolledinfection (defined as paravalvular extension, abscess,or persistent bacteremia), or recurrent embolism. Fora specific patient, there is often debate, for example,in cases of mild heart failure or regarding the defini-tion of persistent bacteremia (109). Current

TABLE 3 Indications for Surgery in AHA and ESC Guidelines

AHA Guidelines 2015 (89)Class, Levelof Evidence ESC Guidelines 2015 (68)

Class, Levelof Evidence Timing†

Heartfailure

Early surgery* is indicated in patients with IE who presentwith valve dysfunction resulting in symptoms orsigns of HF

I, B Aortic or mitral NVE, or PVE with severe acuteregurgitation, obstruction, or fistula causingrefractory pulmonary edema or cardiogenicshock

I, B Emergency

Early surgery* is indicated in patients with PVE withsymptoms or signs of HF resulting from valve dehiscence,intracardiac fistula, or severe prosthetic valve dysfunction

I, B Aortic or mitral NVE, or PVE with severeregurgitation or obstruction causing symptomsof HF, or echocardiographic signs of poorhemodynamic tolerance

I, B Urgent

Uncontrolledinfection

Early surgery* is indicated in patients when IE is complicatedby heart block, annular or aortic abscess, or destructivepenetrating lesions

I, B Locally uncontrolled infection (abscess, falseaneurysm, fistula, enlarging vegetation)

I, B Urgent

Early surgery* is reasonable for patients with relapsing PVE IIa, C

Early surgery* should be considered, particularly in patients withIE caused by fungi or highly resistant organisms (e.g., VRE,multidrug-resistant gram-negative bacilli)

I, B Infection caused by fungi or multiresistantorganisms

I, C Urgent/elective

Early surgery* is indicated for evidence of persistent infection(manifested by persistent bacteremia or fever lasting>5–7 d, and provided that other sites of infection andfever have been excluded) after the start of appropriateantimicrobial therapy

I, B Persisting positive blood cultures despiteappropriate antibiotic therapy and adequatecontrol of septic metastatic foci

IIa, B Urgent

PVE caused by staphylococci or non-HACEKgram-negative bacteria

IIa, C Urgent/elective

Preventionofembolism

Early surgery* is reasonable in patients who present withrecurrent emboli and persistent or enlarging vegetationsdespite appropriate antibiotic therapy

IIa, B Aortic or mitral NVE, or PVE with persistentvegetations >10 mm after $1 embolic episodedespite appropriate antibiotic therapy

I, B Urgent

Early surgery* is reasonable in patients with severe valveregurgitation and mobile vegetations >10 mm

IIa, B Aortic or mitral NVE with vegetations >10 mm,associated with severe valve stenosis orregurgitation, and low operative risk

IIa, B Urgent

Early surgery* may be considered in patients with mobilevegetations >10 mm, particularly when involving the anteriorleaflet of the mitral valve and associated withother relative indications for surgery

IIb, C Aortic or mitral NVE, or PVE with isolated verylarge vegetations (>30 mm)

IIa, B Urgent

Aortic or mitral NVE, or PVE with isolated largevegetations (>15 mm) and no other indicationfor surgery

IIb, C Urgent

*Defined as “during initial hospitalization and before completion of a full course of antibiotics.” †Defined as: emergency surgery ¼ performed within 24 h; urgent surgery ¼ within a few days;elective surgery ¼ after at least 1 to 2 weeks of antibiotic therapy.

HACEK ¼ Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; HF ¼ heart failure; NVE ¼ native valve infective endocarditis; PVE ¼ prostheticvalve infective endocarditis; VRE ¼ vancomycin-resistant Enterococcus; other abbreviations as in Tables 1 and 2.


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indications for surgery, as defined in the AHA andESC guidelines, are shown in Table 3.

In real-world situations, a significant number ofpatients with a guideline indication for interventionstill do not undergo surgery (i.e., 24% [202 of 863] ofpatients with left-sided IE and a guideline indicationfor intervention in the ICE-PCS [InternationalCollaboration on Endocarditis–Prospective CohortStudy] registry) (108). Predictors of nonsurgicaltreatment were liver disease (odds ratio [OR] forsurgery: 0.16; 95% CI: 0.04 to 0.64), stroke beforesurgical decision (OR: 0.54; 95% CI: 0.32 to 0.90), andS aureus infection (OR: 0.50; 95% CI: 0.30 to 0.85). Incontrast, severe aortic regurgitation, abscess, andembolization were associated with surgery. Reasonsfor avoiding surgery in 181 patients included ananticipated poor prognosis regardless of treatment(34%), hemodynamic instability (20%), death beforesurgery (23%), stroke (23%), sepsis (21%), and surgeondeclined to operate (26%). Ultimately, the perceivedrisk of the operation determines the threshold for

surgery; operations for active IE present high risk,with an overall in-hospital mortality of 20% (andhigher still in many centers).

Improved risk-scoring models for IE would help toclarify the decision-making process. Gaca et al. (110)used the Society of Thoracic Surgeons’ databaseto derive an IE surgical risk score, identifying 13risk factors for mortality, including emergencystatus, cardiogenic shock, hemodialysis, and “activeendocarditis.” Other, smaller cohorts have incorpo-rated more detailed parameters of infection, includingvalve type and organism (111,112). The PALSUSE scoreincludes age $70 years, substantial intracardiacdestruction, staphylococcal infection, urgent surgery,female sex, and EuroSCORE (European System forCardiacOperative Risk Evaluation)$10 as predictors ofin-hospital mortality, with in-hospital mortalityranging from 0% in patients with a score of 0, to 45% inpatients with a score >3 (112).

The optimal timing of surgical intervention is alsocontentious. Delaying surgery may allow a longer

TABLE 4 Twenty Years of RCTs in IE, 1996 to 2016

Firs Author, Year (Ref. #) Research Question Patient Population Conclusions

Kang et al., 2012 (126) What is the role of early surgery (within48 h of randomization) in NVE?

Adult patients with left-sided NVE,severe valve disease and largevegetations

Early surgery reduced the composite endpoint ofin-hospital death and embolic events within 6 weeksfrom 23% to 3% (driven by a reduction in embolism)

Fowler et al., 2006 (92) Comparison of daptomycin vs.vancomycin or anti-staphylococcalpenicillin with low-dose gentamicinfor bacteremia or IE caused byStaphylococcus aureus

Adults with S aureus bacteremiaor IE. Patients with intravascularmaterial not intended to beremoved within 4 d or highlikelihood of valve replacementsurgery or death excluded

Daptomycin was noninferior for the primary endpoint ofclinically successful treatment (defined as lack ofclinical failure, microbiological failure, death, failure toobtain blood culture specimen at follow-up, receipt ofpotentially effective nonstudy antibiotics, orpremature discontinuation of the study medication).Clinically significant renal dysfunction occurredin 11% of patients who received daptomycin andin 26% of patients who received standard therapy(p ¼ 0.004)

Chan et al., 2003 (147) Does aspirin reduce the incidenceof embolism in patientswith IE?

Adults with left-sided endocarditis(NVE or PVE). Patients withexpected surgical interventionwithin 7 days excluded

Aspirin did not reduce the risk of embolic events andcaused a nonsignificant trend toward increasedincidence of bleeding

Fortún et al., 2001 (148) Is a short course of glycopeptide(vancomycin or teicoplanin) andgentamicin as effectiveas combination cloxacillin andgentamicin for treatment of right-sidedNVE caused by methicillin-sensitiveS aureus?

Adult IVDUs with right-sided NVEcaused by MSSA

Glycopeptide therapy is inferior to cloxacillin

Sexton et al., 1998 (149) Is ceftriaxone plus gentamicin (for 2 weeks)superior to ceftriaxone alone (for 4weeks) for IE due to penicillin-sensitivestreptococci?

Adults with penicillin-sensitive NVE Equivalent clinical cure in both groups

Ribera et al., 1996 (91) Is cloxacillin alone as effective as cloxacillinplus gentamicin in a 2-week course fortreatment of right-sidedS aureus endocarditis in IVDUs?

Adult IVDUs with isolated tricuspidvalve endocarditis caused by MSSA

No significant benefit from addition of gentamicin tocloxacillin (92% cure in 2-week cloxacillin group, 8%required prolonged treatment)

Heldman et al., 1996 (98) Is oral ciprofloxacin/rifampicin treatment ofright-sided staphylococcal endocarditisin IVDUs as effective as parenteraltherapy (oxacillin or vancomycin, plusgentamicin for the first 5 days)?

Adult IVDUs with right-sidedstaphylococcal endocarditis

Oral therapy is as effective as parenteral treatment andassociated with reduced drug toxicity

IVDU ¼ intravenous drug user; MSSA ¼ methicillin-sensitive Staphylococcus aureus; RCT ¼ randomized controlled trial; other abbreviations as in Tables 1 and 3.



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duration of antibiotic therapy and hemodynamicstabilization but incurs the risk of disease progressionwith valve destruction, abscess formation, heartblock, embolic complications, and even death.Indeed, for some outcomes (e.g., embolism) the po-tential gains from surgery are reduced with time (56).In 2012, the first RCT of surgery for IE compared earlysurgery (undertaken within 48 h of randomization)with conventional care in patients with NVE, severevalve regurgitation, and large vegetations (126). TheSouth Korean study cohort was young (mean age 47years), with little comorbidity and predominantlystreptococcal infection. Early surgery was associatedwith a significant reduction in the compositeendpoint of in-hospital death or embolism (entirelydriven by a reduction in embolism). Furthermore,>90% of patients in the conventional care groupeventually required surgery, thereby validating pre-sent indications for intervention. This study is alandmark achievement for research in IE and hasencouraged a trend toward early surgery, but its

findings are of uncertain applicability in older pop-ulations with multiple comorbidities and staphylo-coccal infection. Studies from the ICE-PCS registry,which define early surgery as that undertaken “withinthe course of the initial hospitalization for IE,” haveshown conflicting results. Although early surgery forNVE is associated with reduced mortality, this sce-nario does not hold true for PVE after adjustment forconfounding variables, including survivor bias (i.e.,the increased likelihood of patients who survive toundergo surgery) (113–115).

The emphasis on “early surgery” differs signifi-cantly between European and U.S. guidelines.The ESC guidelines distinguish emergency surgery(performed within 24 h), urgent surgery (within a fewdays), and elective surgery (after 1 to 2 weeks ofantibiotic therapy), with surgery advised on an urgentbasis for the majority of cases (68). In contrast, theAHA guidelines define early surgery as “during initialhospitalization and before completion of a full courseof antibiotics.” Our conclusion at this time is that

TABLE 5 Studies of IE After TAVR

First Author,Year (Ref. #) No. of TAVR-IE Patients

1-Yr Incidenceof TAVR-IE Microbiology

In-HospitalMortality

1-YrMortality

Aung et al., 2013 (150) 4 (cohort of 132) 3.0% Enterococci (75%), oralstreptococci (25%)

0% 0%

Amat-Santos et al.,2015 (12)

53 (cohort of 7,944) 0.5% CoNS (24%), Staphylococcus aureus (21%),enterococci (21%), oralstreptococci (5.7%)

47% 66%

Bosmans et al.,2011 (151)

2 fatal cases (cohort of328)

0.61% Not reported Not reported 100%

Latib et al., 2014 (152) 29 (cohort of 2,572) 0.89%* Enterococci (21%), CoNS (17%), S aureus(14%), oral streptococci (3.4%)

45% Not reported

Mangner et al., 2016 (13) 55 (cohort of 1,820) 2.25%* S aureus (38%), enterococci (31%), CoNS(9.1%), oral streptococci (3.6%)

64% 75%

Olsen et al., 2015 (153) 18 (cohort of 509) 3.1% Enterococci (33%), S aureus (17%), oralstreptococci (17%), CoNS (11%)

11% Not reported

PARTNER A, 2011 (118) 3 (cohort of 344) 0.87%* Not reported Not reported 33%

PARTNER B, 2010 (117) 2 (cohort of 179) 1.12%* Not reported Not reported 100%

Puls et al., 2013 (154) 5 (cohort of 180) 2.78% Enterococcus (40%), oral streptococci (20%),S aureus (20%), E. coli (20%)

40% 40%

Regueiro et al.,2016 (119)

250 (cohort of 20,006) 1.1% perperson-year

Enterococcus (25%), S aureus (24%),CoNS (17%)

36% 66.7% (2-yrmortality)

Thomas et al., 2011 (155) 99.0% free of IE at 1 yr(cohort of 1,038)

0.1% Not reported Not reported 3 deathsreported

*Calculated/estimated.

CoNS ¼ coagulase-negative staphylococci; IE ¼ infective endocarditis; PARTNER ¼ Placement of Aortic Transcatheter Valve; TAVR ¼ transcatheter valve replacement.


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there is no proven benefit in delaying surgery once anindication for intervention has been established.Whether this surgery is undertaken the same day orwithin 48 h depends on the individual clinical cir-cumstances and availability of appropriate surgicalexpertise. Current series show that very low mortalitycan be achieved in centers of excellence with high-level experience of the management of complex pa-tients and concentrated expertise in cardiology,microbiology, and surgery (106,116).

Resolving the controversy of early surgery requiresrobust evidence to move the field forward. RCT-leveldata are required to drive practice change, which isharder to progress on the basis of observational dataalone. In the last 20 years, only 7 RCTs involvingpatients with IE have been published, the majority ofwhich have focused on antibiotic therapy (Table 4).The first stage is to carefully define the priorities fornew RCTs that are reasonable and acceptable to themedical community. Multicenter studies are chal-lenging, as experience and outcomes vary greatlybetween centers, whereas few have the volume toperform such studies in isolation. Furthermore, un-resolved issues, such as early surgery, may be leftbehind as competing research priorities emerge. Forexample, should PVE be considered as a uniformlysurgical disease? Should all patients with IE and se-vere valve dysfunction have surgery, even if they arenot in heart failure? San Román et al. (109) haveproposed a trial of patients with left-sided IE and

high-risk features (but not classical surgical in-dications) randomized to undergo surgery within 48 hor receive conventional care, with mortality as theprimary endpoint. Although logistically challenging,this study would be extremely valuable and mayherald a long-awaited shift from observationalstudies to RCT-level research.

CONTEMPORARY MANAGEMENT CHALLENGES IN IE.

IE af ter TAVR. TAVR has transformed the outlook forpatients with aortic stenosis who were previouslydeemed inoperable or at high risk for surgery.Although the technology looks set to expand tointermediate-risk populations over time, currentTAVR patients are often frail, undergoing multiplehealth care interventions, and may therefore be athigh risk of bacteremia and IE. The TAVR-endocarditis population represents a commonchallenge to cardiologists and surgeons managingcontemporary IE, namely, how should we managePVE in patients who are elderly and at high risk ofsurgery but with expected poor outcome if managedmedically?

Small numbers of cases of TAVR-endocarditis werereported in the seminal PARTNER (Placement of AorticTranscatheter Valve) trials (117,118), and real-worldcohorts are now starting to shed light on incidenceand outcomes (Table 5). Amat-Santos et al. (12)described 53 patients with TAVR-endocarditis in amulticenter U.S. registry, representing an overall



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incidence of 0.67%at amean follow-up of 1.1 years. Theincidence of TAVR-endocarditis was 0.5% in the firstyear post-procedure, occurring at a median time pointof 6months. More than 70% of patients presented withfever, and 77% had an identifiable vegetation onechocardiography. An antecedent procedure wasidentified as the likely cause of bacteremia in approx-imately one-half of patients, and antibiotic prophy-laxis had been used in 59% of cases. Infectionwasmostcommonly due to staphylococci (CoNS 25%; S aureus21%; and enterococci 21%). Although the self-expanding CoreValve system (Medtronic, Minneap-olis, Minnesota) was an independent risk factor for IE(hazard ratio [HR]: 3.1; 95% CI: 1.37 to 7.14), this findingrequires validation in other series.

Mangner et al. (13) described 55 patients with TAVR-endocarditis from a single center in Germany, repre-senting a cumulative incidence of 3.02% (1.82% perpatient-year); 42% of the cases (23 of 55) were healthcare acquired. On multivariate analysis, chronichemodialysis and peripheral arterial disease weresignificant risk factors for the development of subse-quent TAVR-endocarditis (chronic hemodialysis—HR:8.37; 95%CI: 2.54 to 27.63; p<0.001; peripheral arterialdisease—HR: 3.77; 95% CI: 1.88 to 7.58; p < 0.001).Infection was caused by S aureus in 38% of cases,enterococci in 31%, CoNS in 9%, and streptococci in9.1% of cases. In 7 patients, a valve other than the TAVRprosthesis was infected.

Most recently, 250 cases from the Infective Endo-carditis after TAVR International Registry were re-ported from 47 centers worldwide (119). The overallincidence was 1.1% per person-year, presenting at amedian time of 5.3 months’ post-procedure. Onmultivariate analysis, predictive factors were youngerage (HR: 0.97 per year; 95% CI: 0.94 to 0.99), male sex(HR: 1.69; 95% CI: 1.13 to 2.52), diabetes mellitus (HR:1.52; 95% CI: 1.02 to 2.29), and moderate-to-severeaortic regurgitation (HR: 2.05; 95% CI: 1.28 to 3.28).Infective organisms were enterococci in 24.6% and Saureus in 23.3%. The in-hospital mortality rate was36%, and 2-yearmortalitywas 67%. Additional patient-and device-related factors contributing to increasedrisk of endocarditis are likely to be identified and mayalso teach us more about the nature of endocarditis.The apparently high incidence may also be due tofront-loaded risk in the early months after the pro-cedure, and longer follow-up will be required tocompare outcomes with surgical valve replacement.

Management of TAVR-endocarditis is highly chal-lenging. It remains to be shown whether trans-catheter techniques can be used successfully in itsmanagement without removal of the infectedimplant. Many of these patients were considered high

risk or very high risk for surgery before undergoingTAVR. Indeed, <20% of patients underwent eitheropen-heart surgery or a transcatheter valve-in-valveprocedure in the studies to date. Meanwhile, out-comes with antibiotic therapy alone are extremelypoor, with in-hospital and 1-year mortality rangingfrom 47% to 64% and 66% to 75%, respectively. Thesedata underscore the importance of developing betterpreventive strategies in terms of valve design andprevention of bacteremia.

STROKE AND IE. IE is complicated by stroke in 20%to 40% of cases (120,121). In addition to causing var-iable neurological disability, stroke is an independentadverse prognostic factor for survival (120,122). Therisk of stroke is highest at diagnosis and decreasesrapidly after the initiation of antibiotic therapy(incidence drops from 4.82 per 1,000 patient-days inthe first week of therapy to 1.71 per 1,000 patient-daysin the second week) (56). Identified risk factors forembolism are vegetation size (>10 to 15 mm), mitralvalve involvement, vegetation mobility, and S aureusinfection (123–125).

A key unresolved challenge in the contemporarymanagement of IE is the role of surgery in preventionof stroke/embolism and selection of patients for suchsurgical intervention. The 2015 update to the AHA/ACCguidelines provided a Class IIa indication for surgery toprevent recurrent embolism in patients with $1 pre-vious emboli and ongoing high risk of further embo-lism (defined as persistent or enlarging vegetations)(89). Similarly, the ESC guidelines provide a Class Irecommendation for surgery to prevent recurrentemboli in patients with a persisting vegetation>10mmin size (68). On the basis of RCT evidence, bothguidelines indicate a Class IIa recommendation forsurgery in patients at risk of first embolism (vegetation>10 mm in size) when associated with severe valvularregurgitation or stenosis (126). Surgery for preventionof embolism (in the absence of valve dysfunction) maybe considered in patients at highest risk(e.g., vegetations >15 mm) but is rarely undertaken inmost institutions for this indication alone.

The optimal timing of surgical intervention in pa-tients who have already had a stroke is contentious,with a number of older studies suggesting poor out-comes from early surgery (107). There is a risk ofhemorrhagic transformation caused by anti-coagulation therapy for cardiopulmonary bypass, andhypotension during surgery might theoreticallyworsen cerebral ischemia. Observational studies havetypically been small and inadequately controlled forconfounding variables (120,121). In the largest studyfrom the ICE-PCS collaboration, the outcome from

FIGURE 3 Cardiac CT and 18FDG-PET/CT Imaging in the Diagnosis of CDI

Pacemaker lead IE in a young man with congenital atrioventricular block. On TEE, vegetations were seen on the pacemaker leads (A and B, white arrow). On CT imaging,

vegetations were seen on the pacemaker lead (C, white arrow) with an accompanying pulmonary embolism (D, red arrow). Confirmation of active pacemaker

endocarditis was provided by 18FDG-PET/CT imaging, with uptake seen on the pacemaker lead (E, white arrow) and within the pulmonary vascular tree (F, red arrow).

CDI ¼ cardiac device infection; RA ¼ right atrium; SVC ¼ superior vena cava; other abbreviations as in Figures 1 and 2.


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58 patients with an ischemic stroke undergoing earlysurgery (<7 days) was compared with late surgery.After risk adjustment, surgery was associated with anonsignificant increase in the risk of in-hospitalmortality (OR: 2.3; 95% CI: 0.94 to 5.65) (121). Thisfinding has been interpreted by both the AHA and ESCto suggest that surgery can be undertaken safely ifrequired, although stroke remains a common reasonfor lack of surgical intervention in everyday practice(108). In contrast, transient ischemic attack or silentembolism should not delay surgery that is indicatedfor other reasons (120). Conversely, patients withcerebral hemorrhage or complex stroke (causingcoma) have significantly higher surgical mortality,and surgery should be deferred for at least 4 weeks ifindicated in these patients (125,127). The plan of ac-tion for patients with minor bleeding or minor hem-orrhagic conversion of an ischemic stroke remainsopen to clinical judgment. Clinical scenarios are oftencomplex, and the risk and benefit equation oftenchallenges any rigid recommendation.CARDIAC DEVICE INFECTION. CIEDs include per-manent pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapydevices. The number of CDIs in the United States hasincreased out of proportion to the increase in im-plantation rates (128). Overall, the incidence of CDIafter first implantation is 1 to 10 per 1,000 device-years (approximately 1 per 1,000 device years forpacemakers and 8 to 9 per 1,000 device-years for

complex devices) (129–131). Patients with CDIshave increased short- and long-term morbidity andmortality, and the incremental cost of managementis estimated at more than $15,000 per patient(132,133).

CDI may involve the generator pocket, deviceleads, or endocardial (valve or nonvalve) surfaces (orany combination of these locations). Pocket in-fections are characterized by cellulitis, erythema,wound discharge, and pain, and there may be incip-ient or overt erosion of the skin overlying the pocket.Infection involving CIED leads or the endocardialsurface (CIED-IE) is characterized by systemic fea-tures (e.g., fevers, rigors), and frequently coexistswith pocket infection. IE may originate from a pocketinfection or occur by seeding of infection to the leadsvia the bloodstream. Staphylococci (particularlyCoNS) account for 60% to 80% of cases (134).

Risk factors for CDIs may be patient-, procedure-, ordevice-related factors (135). Patient-specific risk fac-tors include corticosteroid use, diabetes mellitus, end-stage kidney disease, previous device infection,chronic obstructive pulmonary disease, malignancy,and heart failure. Procedural risk factors are thedevelopment of a post-operative hematoma (OR: 8.46;95% CI: 4.01 to 17.86), reintervention for leaddisplacement, long procedure times, and implantationof$2 leads. Need for a revision procedure is associatedwith a 2- to 5-fold higher risk of infection than theinitial implantation. Use of antibiotic prophylaxis has

CENTRAL ILLUSTRATION Infective Endocarditis: Preventive Strategies, Diagnosis, and Management

Preventive strategies Improving diagnosis Optimal management

Reduce hospital acquired bacteremia

Good oral hygienefor at-risk groups

Antibiotic prophylaxisfor high risk groups

In future, antibacterial coatings/materials

High index of clinical suspicion in at-risk groups

Patient education

Early echocardiography

Adjunctive imaging if echocardiography non-diagnostic

Rapid microbiology results with antibacterial sensitivity

Evaluation by anendocarditis team

Early risk stratification

Early transfer tocenter of expertise

Tailored antibiotic therapy

Early surgery forselected patients

Monitoring for complications

Cahill, T.J. et al. J Am Coll Cardiol. 2017;69(3):325–44.



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been shown to protect against CDI in both RCTs andobservational studies (136).

Diagnosis of CIED-IE is made on the basis of echo-cardiography and blood culture results, with TEEhaving better sensitivity and specificity than TTE fordetection of lead vegetations (137). Importantly, ster-ile clots are seen in a high percentage of CIED patientswithout infection, and these lesions are indistin-guishable from infected vegetations (138). In cases inwhich echocardiography is negative or equivocal,radiolabeled leukocyte scintigraphy or 18FDG-PET/CTscans are highly valuable, and they may become thedefinitive investigation on the basis of a number ofstudies demonstrating high sensitivity and specificityfor infection (Figure 3) (139–141). However, there isevidence that 18FDG-PET/CT imaging may yield afalse-negative result for CIED-IE (i.e., lead involve-ment) if patients have received previous antibiotictherapy. In 1 study, 9 of 13 patients had a false-negative scan for CIED-IE (sensitivity 30.8%) (141).Further studies are required to assess the time courseover which the diagnostic value of 18FDG-PET/CT im-aging is preserved.

Strategies for the prevention and management ofCDI are beyond the scope of the present review butare covered in detail by recent guidelines (142). IfCIED-IE is confirmed, complete removal of theinfected system is indicated because medical therapy

alone is associated with increased risk of recurrenceand mortality (142,143). Percutaneous extraction isusually feasible but associated with a major compli-cation rate of 1.9% (144). Prolonged antibiotic therapyis advised, and blood culture findings should benegative for at least 72 h before reimplantation if anew device is essential.

CONCLUSIONS

The challenges of IE are diverse, but many are trac-table (Central Illustration). Prevention is undoubtedlybetter than cure. Translating advances in materialsscience into prosthetic devices with reduced sus-ceptibility to bacterial adhesion would be revolu-tionary. Understanding the relative importance ofdental procedures for patients with known cardiacrisk factors would help direct use of antibiotic pro-phylaxis. The value of integrated diagnostic strate-gies using multimodality imaging is emerging andneeds refinement on the basis of real-world patientcohorts. Surgical treatment plays an increasing role,but the current wide variation in outcomes suggeststhat management should be concentrated in largervalve centers of excellence. Further improving thequality and breadth of the evidence base throughnew RCTs is essential. At the time of writing, only 6RCTs in IE are shown as currently recruiting. Trials


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may be difficult to design but are eminently achiev-able and could be used to assess novel antibioticstrategies, as well as indications for surgery andoptimal timing of surgery. The ESC and AHA, incollaboration with the surgical societies, are wellplaced to host and coordinate such studies, whichwill need to be multicenter and multinational indesign and rely on noncomposite, hard endpoints,

such as mortality. Now is the time to transform cur-rent challenges in IE into answers.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Bernard D. Prendergast, Department of Cardiology,St. Thomas’ Hospital, Westminster Bridge Road,London SE1 7EH, United Kingdom. E-mail: [email protected].

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KEY WORDS cardiac device infection,infective endocarditis, TAVR





































































































































































































Challenges in Infective Endocarditis · THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW Challenges in Infective Endocarditis Thomas J. Cahill, MBBS,a Larry M. Baddour, MD,b Gilbert

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